This application addresses the development of strategies for the sustainable control of tsetse fly-transmitted African trypanosomiasis, which is highly Neglected Tropical Disease (NTD) in sub-Sahara Africa that has plagued human and animal health for decades. Human disease (HAT) caused by African trypanosome parasites are fatal, while the animal disease (AAT) caused by related parasites impede agricultural development and restrict nutrition and economic prosperity for millions of people living in tsetse-infested areas, including in Kenya. No mammalian vaccines exist, and current trypanocidal drug treatments have undesirable side effects with growing reports of treatment failures. As active surveillance campaigns for disease control will no longer be economically sustainable, disease endemic countries (DECs), such as Kenya, must develop and implement programs during periods of low endemicity to prevent the emergence of future epidemics. The most effective current HAT/AAT control methods involve reduction of tsetse vector populations. While vector control can reduce disease, its implementation over vast areas infested by tsetse can be cost prohibiting unless the efficiency of the traditional tools used (traps and targets) can be improved Additionally, a strategic plan must be developed to identify the control target units and their dynamics over time and space to prevent recolonization of cleared lands with flies from neighboring sites. Yale University and the Kenyan Agricultural Research Institute-Trypanosomiasis Research Center (KARI-TRC) scientists have been collaborating to build capacity in Kenya on biomedical research expertise to address parasite transmission biology, genetics of vector competence, chemical ecology, population biology and bioinformatics related to tsetse vectors and trypanosome parasites, and to promote scientific evidence-driven public health policy decisions. This application is a product of this successful collaboration to develop two research projects with immediate translational applications for HAT control. We will: (1) Expand the toolbox available for tsetse population control: These studies will 1) exploit recent genomic and functional genetic discoveries to understand tsetse's chemosensory physiology and identify and test new odors to improve the efficiency of traps and targets used for tsetse population control, and 2) evaluate the cost-effectiveness of using these enhanced control tools for tsetse population reduction. (2) Develop a Decision Support System (DSS) to monitor tsetse transmitted disease risk in Kenya. This project will develop an epidemiologically relevant DSS based on levels of genetic connectivity among tsetse vector populations, habitat suitability that accounts for the functional connectivity between tsetse populations, circulating parasite prevalence and strain diversity as well as tsetse microbiota composition. A mathematical disease transmission model will be developed to evaluate the probability of HAT re-emergence in Kenya based on spatiotemporal dynamics of tsetse and surveillance data obtained.